Iranian Journal of Pharmaceutical Research
Volume:12 Issue: 2, Spring 2013

The cannabinoidergic system acquired a reputation as the most abundant G-protein coupled receptor in the CNS that acts as retrograde modulator of neurotransmitter release. Recently, endocannabinoids (ECBs) have been highlighted as neurodevelopmental signaling cues that exert a regulatory role in brain development. The interruption in ECB system elements (including receptors and enzymes of synthesis and degradation) in the developing brain is in relation with postnatal CNS pathophysiology. The rapid rates of ECB synthesis/degradation reveal the existence of a dynamically regulated ECB tone during the active neurogenesis.

Severe sepsis and septic shock are major problems as the result of high rates morbidity and mortality in intensive care units (ICUs). In the presence of septic shock, each hour of delay in the administration of effective antibiotics is associated with a measurable increase in mortality. Aminoglycosides are effective broad-spectrum antibiotics that are commonly used in ICUs for the treatment of life-threatening Gram-negative infections and as a part of empiric therapy for severe sepsis and septic shock. Knowledge of the pharmacokinetic (PK) and pharmacodynamic (PD) properties of the antibiotics used for the management of critically ill patients is essential for selecting the antibiotic dosing regimens and improving patient outcome. Volume of distribution (Vd) and clearance (CL) of aminoglycosides in critically ill patients differs from general population and these parameters change considerably during the therapy.Pathophysiological changes during the sepsis alter the pharmacokinetic and pharmacodynamic profile of many drugs (increase in Vd and variable changes in CL have been reported for aminoglycosides during the sepsis), therefore, dosing regimen optimization is necessary for achieving therapeutic goal, and critically ill patients should receive larger loading doses of aminoglycosides in order to achieve therapeutic blood levels and due to the considerable variation in kinetic parameters, the use of standard doses of aminoglycosides or dosing nomograms is not recommended in these populations.

The aim of the present study was to investigate the influence and the mechanisms of cineole and terpineol on the in-vitro transdermal delivery of huperzine A from microemulsions, and their potential synergistic effect on the permeation enhancement. The transdermal delivery of huperzine A from microemulsions with different concentrations of cineole and terpineol through the rat abdominal skin was determined by Franz-type diffusion cells. The partition coefficient of huperzine A between the full thickness skin and microemulsion was determined. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) was carried out to analyze the effects of cineole and terpineol on the biophysical properties of the stratum corneum (SC) and the mechanisms of permeation enhancement. These results indicated that cineole and terpineol could synergistically increase the transdermal delivery of huperzine A from microemulsions through increasing the partition and diffusion coefficients of huperzine A. ATR-FTIR studies further validated the synergistic effect and revealed that the enhancing mechanisms were due to increasing the disorderliness and fluidity of SC lipid alkyl chains, disrupting the structure of keratin in SC, and extracting SC lipids. In conclusion, cineole and terpineol, acting synergistically to enhance the transdermal delivery of huperzine A from microemulsions, might provide an alternative permeation enhancer combination for the transdermal delivery of huperzine A.

Chitosan-graft-polyethylenimine (CHI-g-PEI) copolymer has been used for the improvement of low transfection efficiency of chitosan. The present study aims to test the pulmonary toxicity and efficiency of CHI-g-PEI as an aerosol gene carrier. Mice were exposed to aerosol containing green-fluorescent protein (GFP)-polyethylenimine (PEI) or GFP-CHIg- PEI complexes for 30 min during the development of our nose-only exposure chamber (NOEC) system. CHI-g-PEI-mediated aerosol delivery demonstrated 15.65% enhancement of the fluorescence intensity. Compared to PEI, CHI-g-PEI showed no significant pulmonary toxicity. In summary, using CHI-g-PEI is safe and shows high transfection in aerosol gene delivery to animals, and enhanced efficiency was achieved through our aerosol gene delivery system. Therefore, CHI-g-PEI and this system would be applicable to future study for aerosol gene therapy.

A stability indicating High-Performance Liquid Chromatography (HPLC) method was validated and used to study the degradation of cetirizine dihydrochloride in acidic and oxidative conditions. The separation was carried out on a Symmetry C18 column and a mixture of 50 mM KH2PO4 and acetonitrile (60:40 v/v, pH = 3.5) was used as the mobile phase. The method was linear over the range of 1-20 μg/mL of cetirizine dihydrochloride (r2 > 0.999) and the withinday and between-day precision values were less than 1.5%. The results showed that cetirizine dihydrochloride was unstable in 2 M HCl and 0.5% H2O2. The kinetics of the acidic degradation showed a pseudo-first-order reaction in the temperature range of 70-90°C. In addition, the kinetics of hydrogen peroxide mediated degradation was pseudo-first-order in the temperature range of 50-80°C.

A reliable, rapid and accurate method based on spiked calibration curves and direct sample introduction was developed for determination of 17 pesticide residues in rice by gas chromatography-mass spectrometry single quadrupole selected ion monitoring GC/MS-SQ-SIM. Sample preparation is based on extraction with acetonitrile without clean up. The use of spiked calibration curves for constructing the calibration curve substantially reduced adverse matrix-related effects. The average recovery of pesticides at 6 concentration levels was in range of 97.5-102.1%. The method was proved to be repeatable with RSDr in range of 0.7%-19.8%for all of the concentration levels. The limits of detection and limit of quantifications for all the pesticides were < 10 ng/g and < 25 ng/g, respectively. The developed method was applied for simultaneous determination of the selected pesticides in 23 rice samples collected from Tehran retail market in March 2009. Although many studies have been conducted regarding the determination of pesticides by using GC-MS, this is the first attempt in Iran using GC-MS-SIM technique that successfully can determine 17 pesticides with difference in physicochemical properties in rice.

A simple, accurate and rapid high performance thin layer chromatography (HPTLC)-densitometric method was developed for separation and determination of cetirizine (CET) as a long acting antihistamine and montelukast (MON) as an antileukotriene in pharmaceutical dosage forms. The compounds were separated on silica gel 60 F254 HPTLC plates using a mixture of ethyl acetate: methanol: ammonia solution (25%) (14: 3: 2 v/v/v) as mobile phase. The plates were developed vertically up to a distance of 80 mm. Compact spots of both cetirizine (Rf = 0.30 ± 0.01) and montelukast (Rf = 0.52 ± 0.02) were obtained. UV detection was performed at 230 nm. Quantitative analysis was performed by absorbance densitometry using peak area. The method was validated in terms of linearity, precision, accuracy, limit of detection (LOD), and limit of quantification (LOQ). The calibration curves were linear in the range of 40-2000 ng spot-1 for cetirizine and 120-1000 ng spot-1 for montelukast. For MON, recovery varied in range of 99.20-100.88% with RSD ranging from 1.02 to 1.90% and for CET, recovery varied in range of 98.13-100.05% with RSD ranging from 1.57 to 1.85%. The LODs were found to be 3.94 and 2.08 ng spot-1 for CET and MON, respectively. It was observed that the proposed HPTLC method could be used for efficient analysis and monitoring of the CET and MON in combined tablet dosage forms, more convenient with better precision and accuracy than HPLC method.

Novel dispersive liquid-liquid microextraction (DLLME), coupled with high performance liquid chromatography with photodiode array detection (HPLC-DAD) has been applied for the extraction and determination of cyproheptadine (CPH), an antihistamine, in human urine samples. In this method, 0.6 mL of acetonitrile (disperser solvent) containing 30 µL of carbon tetrachloride (extraction solvent) was rapidly injected by a syringe into 5 mL urine sample. After centrifugation, the sedimented phase containing enriched analyte was dissolved in acetonitrile and an aliquot of this solution injected into the HPLC system for analysis. Development of DLLME procedure includes optimization of some important parameters such as kind and volume of extraction and disperser solvent, pH and salt addition. The proposed method has good linearity in the range of 0.02-4.5 µg mL-1 and low detection limit (13.1 ng mL-1). The repeatability of the method, expressed as relative standard deviation was 4.9% (n = 3). This method has also been applied to the analysis of real urine samples with satisfactory relative recoveries in the range of 91.6-101.0%.

A series of five-membered heterocyclic rings were synthesized by the reaction between benzoyl chloride and various chlolro-nitro-benzoyl chlorides and semi carbazide to form (C1-C7) compounds and was tested for their anti-inflammatory activity determined by rat-paw-oedema method. All the synthesis compounds have been characterized by 1HNMR, IR and Mass spectral data. The compounds were purified by column chromatography. All synthesized derivatives were determined by the carrageenan-induced rat-paw-oedema model for anti-inflammatory activity. The entire compound gives good response for the anti-inflammatory activity: [3-Chloro-N-[5-(3-Chloro-phenyl)-[1,3,4] oxadiazole-2yl] benzamide (C4), and [4-Nitro-N-[5-(4-Nitro-phenyl)-[1,3,4] oxadiazole-2yl] benzamide (C7). For this activity, indometacin was used as a standard drug and compared to new synthesized drugs. Some new synthesized drugs have shown better activities for the anti-inflammation.

The complex metabolic syndrome, diabetes mellitus, is a major human health concern in the world and is estimated to affect 300 million people by the year 2025. Several drugs such as sulfonylureas and biguanides are presently available to reduce hyperglycemia in diabetes mellitus. These drugs have side effects and thus searching for a new class of compounds is essential to overcome this problems. A series of seven novel N-(4-phenylthiazol-2-yl)benzenesulfonamides derivatives were synthesized and assayed in-vivo to investigate their antidiabetic activities by streptozotocin-induced model in rat. These derivatives showed considerable biological efficacy when compared to glibenclamide, a potent and well-known antidiabetic agent, as a reference drug. Four of the compounds were effective, amongst which 13 show more prominent activity at 100 mg/Kg p.o. The experimental results are statistically significant at p < 0.05 level.

In this work, we reported the synthesis and evaluation of antimycobacterial and antifungal activity of a series of thiocarbohydrazone derivatives which are thiacetazone congeners. The target compounds were synthesized in superior yields by reacting thiocarbohydrazide with different aromatic aldehydes and methyl ketones. Compounds 8, 19 and 25 were found to be the most potent derivatives, exhibiting acceptable activity against Mycobacterium bovis BCG compared to thiacetazone and ethambutol as reference substances. Compounds 8, 15 and 25 exhibited the highest activity against Candida albicans. The most active compounds had a completely different aromatic ring system with various electronic, steric and lipophilic natures. This is understandable in light of the fact that carbohydrazone derivatives must undergo a metabolic activation step before exerting their anti-TB activity and different SAR rules govern each one of these two processes.

Ubiquicidin (UBI) [29-41] is a synthetic cationic antimicrobial peptide that preferentially binds to bacterial cell membrane at the site of infection. We aimed to assess diagnostic value of 99mTc-UBI [29-41] as a radiopharmaceutical in differentiation of bacterial infection from sterile inflammation in suspected orthopedic implants. Nine patients suspected for orthopedic implant infection, all males with the mean age of 41.6 ± 20.9 years, were studied. A dose of 10 MBq/Kg (range: 555-740 MBq) 99mTc-UBI [29-41] was injected intravenously. A dynamic study followed by static whole body imaging at 30, 60 and 120 min post-radiotracer injection was acquired. Periprosthetic tissue culture was considered the closest test to a gold standard for diagnosing infections and scintigraphic scans were categorized as true- or false-positive and true- or false-negative, considering the bacterial culture as the gold standard. No adverse reaction was observed during or after the radiotracer injection days. There were five true positive, four true negative and no false positive and false negative scans. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were all calculated as 100%. We found a high diagnostic accuracy for 99mTc-UBI [29-41] scintigraphy in differentiation of bacterial infection from sterile inflammation in suspected orthopedic implants. Therefore, 99mTc-UBI [29-41] scintigraphy might be potentially recommended as a safe and promising imaging modality in these settings. However, further studies on a larger number of patients and different pathologies are still needed.

Breast cancer radioimmunoscintigraphy targeting HER2/neu expression is a growing field of work in nuclear medicine research. In this study, trastuzumab was successively labeled with [67Ga] GaCl3 after conjugation with DOTA-NHS-ester. The conjugates were purified by molecular filtration, the average number of DOTA conjugated per mAb was calculated and total concentration was determined by spectrophotometric method. DOTA-Trastuzumab was labeled with 67Ga. Radiochemical purity, integrity of protein after radiolabeling and stability of 67Ga-DOTA-Trastuzumab were determined followed by biodistribution studies in wild-type rats (30 ± 5.5 μCi, 2, 4 and 24 h p.i.).The radioimmunoconjugate was prepared with a radiochemical purity of higher than 95% (RTLC). The average chelate to antibody ratio (c/a) for the conjugate used in this study was 5.8:1. The final compound was stable in presence of PBS at 37ºC and room temperature. The sample was showed to have similar patterns of migration in the gel electrophoresis similar to the native protein. The accumulation of the radiolabeled antibody in liver, spleen, kidney, heart and other tissues demonstrates. 67Ga-DOTA-Trastuzumab was prepared as a surrogate for important clinically applicable radionuclides used in SPECT and PET including In-111 and Cu-64 as a model of radiolabeling. It is also a potential compound for molecular imaging of SPECT for diagnosis and treatment studies and follow-up of HER2 expression in oncology.

The present study was designed to determine the effects of the essential oil of Laurus nobilis L. (Lauraceae) and its three main components on α-glucosidase and reactive oxygen species scavenging activity. The chemical composition of the essential oil from Laurus nobilis L. leaves was analyzed by GC/GC-MS and resulted in the identification of 29 compounds, representing 99.18% of the total oil. 1,8-cineole (68.82%), 1-(S)-α-pinene (6.94%), and R-(+)- limonene (3.04%) were determined to be the main components. The antioxidant features of the essential oil and its three main components were evaluated using inhibition of 2,2-diphenyl-1- picrylhydrazyl, hydroxyl, and superoxide radicals, inhibition of hydrogen peroxide and lipid peroxidation assays. The results show that the DPPH, hydroxyl, and superoxide radical as well as hydrogen peroxide scavenging activities of the essential oil are greater than the positive controls and the three main components of the oil when tested independently. The inhibition of lipid peroxidation by the oil occurred less frequently than with 1,8-cineole and R-(+)- limonene alone, but the effects were more pronounced than those seen with 1-(S)-α-pinene and the positive controls. An α-glucosidase inhibition assay was applied to evaluate the in-vitro antidiabetic activity of the essential oil. IC50-values were obtained for laurel essential oil, 1, 8-cineole, 1-(S)-α-pinene, and R-(+)-limonene: 1.748 μL/mL, 1.118 μL/mL, 1.420 μL/mL and 1.300 μL/mL, respectively. We also found that laurel essential oil and 1, 8-cineole inhibited the α-glucosidase competitively while 1-(S)-α-pinene and R-(+)-limonene were uncompetitive inhibitors.

Achillea wilhelmsii have been used in folk remedies. The relaxant effects of the extract of A. wilhelmsii on tracheal chains of guinea pigs were examined. The relaxant effects of four cumulative concentrations of the extract, theophylline and saline were examined by their relaxant effects on precontracted tracheal chains of guinea pig by KCl (group 1), 10 μM methacholine (group 2), incubated tissues by atropine, propranolol and chlorpheniramine and contracted by KCl (group 3) and incubated tissues by propranolol and chlorpheniramine and contracted by methacholine (group 4). In group 1 and 2, all concentrations of theophylline and three higher concentrations (4, 6 and 8 mg/mL) of the extract showed significant relaxant effects compared to that of saline. In groups 3 and 4 experiments also all concentrations of the extract showed significant relaxant effects compared to that of saline. The relaxant effect of three higher concentrations (4, 6 and 8 mg/mL) of the extract in group 1 were significantly greater than those of group 2 and in group 3 were significantly lower than those of group 1. There were significant positive correlations between the relaxant effects and concentrations for theophylline in groups 1 and 2 and the extract in all four groups of experiments. These results showed a potent relaxant effect for the extract from A. wilhelmsii on tracheal chains of guinea pigs. A muscarinc receptor blockade was also suggested for the extract.

Neuroprotective effect of the extract from aerial parts of Scrophularia striata Boiss (Scrophulariaceae) was investigated against glutamate-induced neurotoxicity on cultured rat pups Cerebellar Granule Neurons (CGNs). CGNs from 8 days old Sprague-Dawley rat were prepared and cultured. The experiments were performed after 8 days in culture. The plant was collected from the northeastern part (Ruin region) of Iran and air-dried at room temperature. The total extract was prepared with maceration of prepared powder in ethanol 80% for three times. Sequential extracts were obtained using dried and powdered aerial parts with increasingly polar solvents: petroleum ether, chloroform, ethyl acetate and methanol 80% solution. Cultured cells were exposed to 125 μM of glutamate for 12 h following a 24 h of incubation with test fractions at concentration of 10 mcg/mL. Morphological assay was performed using invert light microscope after fixation and staining with haematoxylin. Neuronal viability was measured using MTT assay. Statistical analysis was done using SPSS software. One way analysis of variance (ANOVA) was performed by Tukey post-hoc test. Values were considered statistically significant when p-value ≤ 0.05.Results of this study showed a significant neuroprotective activity of high polarity methanolicfraction of aerial parts of Scrophularia striata against glutamate-induced neurotoxicity in a dosedependent manner. Treatment with 10 mcg/mL of the fractions showed the best result.

Two flavones, ladanein and 6-hydroxy-5,7,4′-trimethoxyflavone and one labdane-type diterpene, ent-13-epi-manoyloxide, were isolated from an ethyl acetate-methanol extract of the aerial parts of Salvia sharifii. The compounds were purified using several chromatographic methods. Structural elucidation of the compounds was performed using their 1H and 13C-NMR data, EI mass and UV spectral data. The compounds have been subjected to antimicrobial, antioxidant and cytotoxic activity. The diterpene showed higher cytotoxic activity than the flavones while the later compounds were better antioxidants compared with the isolated diterpene.

Traditionally, Lactuca sativa (lettuce) has been recommended for its hypnotic property. The present study was planned to investigate sleep-prolonging effect of this plant. The hydroalcoholic extract (HAE) of lettuce and its water fraction (WF), ethyl acetate fraction (EAF), and n-butanol fraction (NBF) were administrated (IP) to mice 30 min before the pentobarbital injection. Moreover, both in-vivo and in-vitro toxicity of the extracts were determined. The quality of HAE and NBF was also evaluated using HPLC fingerprint. The HAE prolonged the pentobarbital-induced sleep duration at dose of 400 mg/Kg. The NBF was the only fraction which could increase the sleep duration and decrease sleep latency. The effects of NBF were comparable to those of induced by diazepam. The LD50-value for HAE was found to be 4.8 g/Kg. No neurotoxic effect was observed either by HAE or by its fractions in cultured PC12 neuron-like cells. The results suggest that lettuce potentiates pentobarbital hypnosis without major toxic effect. The main component(s) responsible for this effect is most likely to be nonpolar agent(s) which found in NBF of this plant.

The objective of the present investigation was to assess the possible involvement of GABAergic mechanism in analgesic effect of aqueous extract of Origanum Vulgare (ORG) in a rat model of acute pain test. Sixty-three anaesthetized male Wistar rats (200-250 g) were cannulated into the left ventricle. Five to seven days after the recovery from surgery, ORG extract was intraventricularly injected at dose of 3 μg/rat i.c.v. Then, baclofen (10 mg/Kg, IP), CGP35348 (100 nmol/Kg, i.c.v), muscimol (1 mg/Kg IP) and bicuculline (5 mg/Kg IP) were separately injected 20 min before the injection of ORG. The experimental groups were compared with intact (control) group (n = 7). The response latency of rats to thermal stimulation was recorded using Tail-Flick test. Injection of ORG extract resulted in a significant and dose-dependent increase in the response latency. There was also a significant increase in the response latency after co-administration of ORG extract with baclofen when compared with control group.However, following co-administration of ORG extract/bicuculline, a significant decrease in the response latency was observed compared to control group. In conclusion, the results of the present study suggest that aqueous extract of Origanum vulgare L. ssp. viridis possesses antinociceptive activity in a dose-dependent manner and ORG-induced antinociception might be mediated, at least in part, by both GABA receptors.

Alzheimer’s disease (AD) is a neurodegenerative disease that was characterized with deposit of beta amyloid (Aβ) aggregate in senile plaque. Oxidative damage to neurons and loss of cholinergic neurons in forebrain region are observed in this disease. Melissa officinalis is a medicinal plant from Lamiaceae family, used traditionally in the treatment of cognitive disorders. It has cholinomimetic and potent antioxidant activity. In the present study, we investigated the possible neuroprotective effects of total ethanolic extract, acidic and non-acidic fraction of Melissa officinalis on Aβ-induced cytotoxicity and oxidative stress in PC12 cells and also measured their in-vitro anticholinesterase activity. PC12 cells were incubated with the extract and fractions prior to the incubation with Aβ and cell toxicity was assessed by MTT assay. In addition, productions of reactive oxygen species (ROS), Malondialdehyde (MDA) as a biomarker of lipid peroxidation and glutathione peroxidase activity were measured. Pretreatment of cells with total extract and acidic fraction (not non-acidic fraction) had protective effect against Aβ-induced oxidative changes and cell death. In concentrations in which both total extracts of an acidic fraction showed neuroprotective effects, inhibition of cholinesterase activity was not significant. Then, the protective effects of Melissa officinalis total extract and acidic fraction were not attributed to their anticholinesterase activity. Acidic fraction showed more potent protective effect compared to the total extract, leading to the fact that polyphenolic compounds and terpenoic acids are the most effective components in the total extract concentrated in this fraction.

Diabetes mellitus is a common endocrine disorder. Anti-diabetic agents from natural and synthetic sources are available for the treatment of this disease. Berberis integerrima is a medicinal shrub used in conventional therapy for a number of diseases. The aim of the present study was to investigate the effects of aqueous extract of Berberis integerrima root (AEBI) on some physiological parameters in normal and streptozotocin-induced (STZ-induced) diabetic male Wistar rats. STZ-induced diabetic rats showed significant increases in the levels of blood glucose, triglycerides (TG), total cholesterol (TC), low density lipoprotein LDL-cholesterol (LDL-C), creatinine (Cr), urea, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin while body weight, high density lipoprotein HDL-cholesterol (HDL-C) and total protein levels were significantly decreased compared to normal rats. Treatment of diabetic rats with different doses of aqueous extract of Berberis integerrima root (250 and 500 mg/Kg bw) resulted in a significant decrease in blood glucose, triglycerides, cholesterol, LDL-cholesterol, ALT, AST, ALP, total bilirubin, creatinine and urea while HDL-cholesterol and total protein levels were markedly increased after six weeks compared to untreated diabetic rats. The effects of the AEBI at dose of 500 mg/Kg in all parameters except blood glucose (similar) is more than to the standard drug, glibenclamide (0.6 mg/Kg, p.o.). The results of this study indicate that the tested aqueous extract of Berberis integerrima root possesses hypoglycemic, hypolipidemic and antioxidant effects in STZ-induced diabetic rats.

Avicennia marina (Avicenniaceae) is a species of mangrove tree used for treatment of small pox lesions in Persian folk medicine. The antiviral activity of methanol, ethanol, water, chloroform and n-hexane extracts was evaluated against HIV-1 and HSV. Methanol extract had the highest antiviral activity and the most polar fraction of this extract (fraction D) inhibited HSV with TI and SI values of 57.1 and 133; however, it showed mild activity against HIV with SI value of 6.25 (fraction 3). The anti-HSV activity of active fraction was confirmed using FLASH-PCR. Phytochemical investigation revealed that fraction D encompasses flavonoids compounds. The time-of-addition study demonstrated that fraction D disturbs viral replication after penetrating to the cell. A. marinawas endowed with fragments by which found to be able to inhibit replication of HSV after entry but did not show significant potency against HIV-1. This promotes further investigation in anti-HSV drug discovery.

Rosmarinus officinalis has been used in traditional medicine extensively. This study evaluated the hormonal and cellular effects of Rosmarinus officinalis extract on testes of adult rats. Thirty male Wistar rats (in three groups) received 50 or 100 mg/Kg b.w of Rosmarinus officinalis extract (made from the plant’s leaves, flower and stem) (treatment groups) and 10 mL/Kg b.w normal saline (control group) respectively, on a daily bases by gavage route for 60 days. Then, spermatological properties, histometric parameters and sperm dynamics, testis and body weight, testicular cell population and serum testosterone level were analyzed by an acceptable method.Results showed that the mean serum testosterone level was decreased significantly in both treatment groups (50 and 100 mg/Kg b.w) during the experiment time, compared with control group (p < 0.05). However, Rosmarinus officinalis did not change the total count, motility and viability of sperm. In addition, Rosmarinus officinalis at both doses did not change body and testes weight and their ratio. Furthermore, Rosmarinus officinalis increased the number of Spermatogonia at both doses, Spermatocyte at doses of 50 mg/Kg b.w, Leydig cell and Spermatid at dose of 100 mg/Kg b.w significantly (p < 0.05). Rosmarinus officinalis did not significantly affect the number of Spermatozoid and Sertoli cells. In conclusion, it seems that Rosmarinus officinalis may have some hormonal and cellular effects on the testes which can contribute the spermatogenesis process in rat. Rosmarinus officinalis may have antiandrogenic effect potentially indicating the possibility of developing herbal male contraceptive.

Two common single nucleotide polymorphisms (SNPs) of the human TLR4 gene, namely Asp299Gly (D299G) and Thr399Ile (T399I), have been shown to impair the ability of certain individuals to respond properly to TLR4 ligands. 5-Fluorouracil (5-FU) is widely used for the treatment of patients with advanced colon cancers. The present study examined the impact of two common polymorphisms of the TLR4 genes on the response of the HCT116 colorectal cancer cells to 5-FU. HCT116 was transfected with Flag-CMV1-TLR4 wild-type (WT) and D299G, T399I expression plasmids. The cytotoxic effect of 5-FU on transfected cells was assessed by MTT assay. FACS analysis was performed to show the effect of 5-FU and LPS on the expression of different variants of TLR4. The lowest IC50-value was measured in cells expressing the WT TLR4 and non-transfected cells were more resistance to the drug compared to the other cells. 5-FU significantly induced the expression of TLR4 protein in the presence and absence of LPS. 5-FU also induced HMGB1 secretion, Cas3 and PARP activity and these effects were stronger in cells expressing WT TLR4 than the other cells. In conclusion, 5-FU-induced TLR4 expression and LPS had synergistic effect with 5-FU to induced apoptosis in colorectal cancer cells.

Catecholamine is a group of neurotransmitters that is believed to be responsible for the normal function of animal brain. Physiological and behavioral changes of human body have been reported due to the damage of the brain function following lead exposure. Due to the assumption of lead disposal in brain tissue with two year for its half-life, which results in alteration of brain function, we investigated the ability of lead to change the brain catecholamines during short and long-term studies. Rats were exposed daily with varying amounts of lead and catecholamine contents of cerebellum, mid-brain and brain cortex were determined. Acute peritoneal administration of single dose of lead as lead acetate (260 µmol/Kg) after 2 h reduced (p < 0.05) the catecholamine levels of cerebellum, mid-brain and cortex part by 34.9%, 35.44% and 23.8%, respectively. The extension of experiment time to 5 h, significant (p < 0.05) reductions in catecholamine levels of mentioned regions of brain by 32.35%, 12.35% and 19.3% were seen respectively. Daily intraperitoneal administration of 10 µmol/Kg lead for 30 and 60 days reduced catecholamines levels of cerebellum (22.22% and 30.44%), mid-brain (12.48% and 26.27%) and brain cortex (11.58% and 26.7%) respectively. It might be concluded that brain dysfunction in lead intoxicated rat occurred through the reduction in the catecholamine levels of different parts of brain. Lead might be therefore considered as a probable factor in causing neurological disease in lead exposed man.

Postpartum hemorrhage is an important cause of maternal morbidity and mortality after delivery. Active management of postpartum hemorrhage by an uterotonic drug decreases the rate of postpartum hemorrhage. The aim of this study is to evaluate the efficacy of rectal misoprostol for prevention of postpartum hemorrhage. This double blind randomized clinical trial was performed on full term pregnant women candidate for vaginal delivery, referred to Zahedan Imam Ali Hospital during 2008-2009. They were randomly divided into two groups of rectal misoprostol and oxytocin. The women in misoprostol group received 400 µg rectal misoprostol after delivery and the women in oxytocin group received 3 IU oxytocin in 1 L ringer serum, intravenously. Rate of bleeding, need to any surgery interventions, rate of transfusion and changes in hemoglobin and hematocrite were compared between two groups. A total of 400 patients (200 cases in misoprostol group and 200 in oxytocin group) entered to the study. Rate of bleeding > 500 cc was significantly higher in oxytocin group than misoprostol group (33% vs. 19%) (p = 0.005). Also, need to excessive oxytocin for management of postpartum hemorrhage was significantly lower in misoprostol group than oxytocin group (18% vs. 30%) (p = 0.003). Decrease in hematocrite was significantly more observed in oxytocin group than misoprostol group (mean decrease of hematocrite was 1.3 ± 1.6 in misoprostol group and 1.6 ± 2.2 in oxytocin group). Two groups were similar in terms of side-effects. Rectal misoprostol as an uterotonic drug can decrease postpartum hemorrhage and also can prevent from decrease of hemoglobin as compared to oxytocin.

PCOS (Polycystic Ovarian Syndrome) is associated with insulin resistance, obesity and disorders of lipid metabolism as well as infertility. Fenugreek seeds extract is successfully used in lowering blood glucose. Metformin has also the same effect but in a different way. The aim of this study was the assessment of fenugreek effects on insulin resistance in women with PCOS.This was a prospective randomized, double-blind, placebo-controlled trial. The study was conducted at the Montaserieh Hospital in Mashhad University of Medical Sciences, Mashhad, Khorasan Razavi Province, Iran. The patient population included 58 oligo-anovulatory PCOS women with typical ovaries. Women were randomly allocated to receive hydroalcoholic extract of fenugreek seeds in capsules with metformin (n = 30) or placebo capsules with metformin (n = 28) and were assessed before and every 4 weeks within a treatment period of 8 weeks.Menstrual disturbance and metabolic parameters (markers of insulin resistance and hormonal parameters) were measured. Insulin resistance based on HOMA-IR (homeostasis model assessment for insulin resistance) model was not significantly different between two groups. Ultrasound scans were performed before and at the end of 8 weeks treatment with significant decrease in PAO (polycystic appearing ovaries) in group 1 (p = 0/01).Adjuvant therapy to the fenugreek seeds extract (with metformin) in PCOS women improved the sonographic results and menstrual cyclicity.

There is no randomized study carried out in order to compare their pharmacokinetic parameters although midazolam, as a sedative, has been widely administered via continuous infusion as well as intermittent bolus doses in mechanically ventilated critically ill patients. We prospectively investigated the effect of these two principal methods on pharmacokinetic parameters in 23 of mentioned patients (16 males, 7 females) with the mean (± SD) age of 41.22 ± 17.5. All patients received total dose of 72 mg throughout the test days, 9 of whom received 1 mg/h (continuous infusion) and the rest obtained 4 mg / 4 h (intermittent bolus doses). Blood samples were collected at 8 and 4 h prior to the end time of drug administration (zero time), zero time and 4, 8, 12, 20 and 30 h after it. APACHE (Acute Physiology and Chronic Health Evaluation) II required data was recorded daily and the patients’ mean score was 16.26 ± 4.38. The mean (± SD) value of pharmacokinetic parameters of Midazolam in continuous infusion and intermittent bolus doses methods were as follows: (t½ = 17.88 ± 14.65 h, Cl = 21.80 ± 14.95 L/h) vs. (t½ = 19.74 ± 12.45 h, Cl = 29.43 ± 19.45 L/h). Volume of distribution (Vd) was measured in continuous infusion group which was 612.58 ± 582.93 L. The calculated clearance and half-life were found not to be significantly different (p < 0.05). The patients might be exposed to similar undesired effects due to the large volumes of distribution following the administration methods studied.